Chapter 062. Principles of Human Genetics (Part 22) pot

Principles of Human Genetics Part 22 Inherited mitochondrial disorders are transmitted in a matrilineal fashion; all children from an affected mother will inherit the disease, but it w

Chapter 062 Principles of

Human Genetics

(Part 22)

Inherited mitochondrial disorders are transmitted in a matrilineal fashion; all children from an affected mother will inherit the disease, but it will not be transmitted from an affected father to his children (Fig 62-11D ) Alterations in the mtDNA affecting enzymes required for oxidative phosphorylation lead to reduction of ATP supply, generation of free radicals, and induction of apoptosis Several syndromic disorders arising from mutations in the mitochondrial genome are known in humans and they affect both protein-coding and tRNA genes (Table 62-1 and Table 62-5) The broad clinical spectrum often involves (cardio)myopathies and encephalopathies because of the high dependence of these tissues on oxidative phosphorylation The age of onset and the clinical course are highly variable because of the unusual mechanisms of mtDNA transmission,

which replicates independently from nuclear DNA During cell replication, the proportion of wild-type and mutant mitochondria can drift among different cells and tissues The resulting heterogeneity in the proportion of mitochondria with and

without a mutation is referred to as heteroplasmia and underlies the phenotypic

variability that is characteristic of mitochondrial diseases

Table 62-5 Selected Mitochondrial Diseases

#

MELAS syndrome: mitochondrial myopathy with

encephalopathy, lactacidosis, and stroke

540000

Leber's optic atrophy: hereditary optical neuropathy 535000

Kearns-Sayre syndrome (KSS): ophthalmoplegia, pigmental

degeneration of the retina, cardiomyopathy

530000

MERRF syndrome: myoclonic epilepsy and ragged-red

fibers

545000

Neurogenic muscular weakness with ataxia and retinitis

pigmentosa (NARP)

551500

Progressive external ophthalmoplegia (CEOP) 258470

Pearson syndrome (PEAR): bone marrow and pancreatic

failure

557000

Autosomal dominant inherited mitochondrial myopathy

with mitochondrial deletion (ADMIMY)

157640

Somatic mutations in cytochrome b gene: exercise

intolerance, lactic acidosis, complex III deficiency, muscle pain,

ragged-red fibers

516020

Acquired somatic mutations in mitochondria are thought to be involved in several age-dependent degenerative disorders affecting predominantly muscle and the peripheral and central nervous system (e.g., Alzheimer's and Parkinson's disease) Establishing that a mtDNA alteration is causal for a clinical phenotype is challenging because of the high degree of polymorphism in mtDNA and the phenotypic variability characteristic of these disorders Certain pharmacologic

treatments may have an impact on mitochondria and/or their function For example, treatment with the antiretroviral compound azidothymidine (AZT) causes an acquired mitochondrial myopathy through depletion of muscular mtDNA

Mosaicism

Mosaicism refers to the presence of two or more genetically distinct cell lines in the tissues of an individual It results from a mutation that occurs during embryonic, fetal, or extrauterine development The developmental stage at which the mutation arises will determine whether germ cells and/or somatic cells are involved Chromosomal mosaicism results from non-disjunction at an early embryonic mitotic division, leading to the persistence of more than one cell line,

as exemplified by some patients with Turner syndrome (Chap 343) Somatic mosaicism is characterized by a patchy distribution of genetically altered somatic cells The McCune-Albright syndrome, for example, is caused by activating mutations in the stimulatory G protein α (Gsα) that occur early in development (Chap 347) The clinical phenotype varies depending on the tissue distribution of the mutation; manifestations include ovarian cysts that secrete sex steroids and cause precocious puberty, polyostotic fibrous dysplasia, café-au-lait skin pigmentation, growth hormone–secreting pituitary adenomas, and hypersecreting autonomous thyroid nodules (Chap 341)